Contrary to previously expected, high fructose (HF) consumption is emerging as a key contributor to the worldwide epidemic of metabolic syndrome (MetS), posing pressing concerns for the lack of understanding of the mechanisms mediating the effects of HF. Considering the broad actions of fructose in peripheral organs as well as in the brain control of energy homeostasis, nutrigenomic approaches capable of revealing the impact of HF on webs of molecular events and their interactions are essential to capture the whole dimensionality of MetS etiology. We hypothesize that HF induces epigenetic variability to alter the organization of gene networks in tissues underlying the MetS pathology, thereby reprograming metabolism and increasing risks for MetS. The information on gene network organization can be utilized to guide interventions to reverse HF-induced reprogramming, leading to regain of control of metabolic homeostasis. We propose an integrative nutrigenomics study that harnesses the power of high throughput genomic technologies and network modeling approaches, coupled with in vivo experimental studies in mice and genetic studies in humans, to reveal the impact of HF on genomic signatures of MetS etiology. This application represents a unique opportunity to synergize the expertise of two complementary multidisciplinary teams - one specialized in genomics and the other specialized in nutritional research - with the merit to combine nutrigenomic approaches and integrative physiology to advance our understanding of the impact of nutrients on the etiology of MetS. In Aim 1, we will use next-generation sequencing technologies to determine the capacity of HF consumption to promote large- scale changes in the DNA methylome as well as in the transcriptome in selected MetS-related tissues in a mouse model, and identify molecular signatures of MetS pathology. In Aim 2, we will assess how high fructose affects the organization of genes in networks, and will identify key regulatory genes that may be responsible for the shifts in the network dynamic. The novel regulators and gene networks identified will be tested for causal association with MetS by i) targeting novel regulatory genes in genetically modified animal models, and ii) assessing novel regulators/networks for genetic association with metabolic diseases in human genome-wide association studies (GWAS). Lastly, in Aim 3, we will address the therapeutic utility of the gene networks by corroborating the capacity of DHA omega-3 fatty acid to normalize epigenetic variability and gene networks disrupted by HF. Our preliminary data indeed support that fructose induces epigenomic and network-level perturbations, which are reversed using DHA. Completion of the study will provide the much needed integrative and systems-level understanding of the basic molecular processes underlying HF-induced MetS pathology. The mechanistic insights obtained will help guide the selection of novel therapeutic targets and the development of network-based nutritional strategies for alleviating the growing health burden of MetS.